Expanding the phenotypic spectrum of MPDZ gene variants: A case report with prenatally detected Dandy-Walker malformation and single ventricle heart.

A 19-year-old gravida underwent genetic counseling at the 26th week of gestation due to sonographically detected fetal anomalies, including Dandy-Walker malformation, characterized by cerebellar vermis hypoplasia and an enlarged cisterna magna, and single ventricle heart. Following amniocentesis at the 27th week, after the normal quantitative fluorescence polymerase chain reaction and chromosomal microarray results, trio clinical exome sequencing was performed, revealing a novel homozygous pathogenic variant in the MPDZ gene, c.4576G>T (NM_001378778.1). So far, homozygous and compound heterozygous variants in MPDZ have been strongly linked to congenital hydrocephalus type 2 with or without accompanying brain or eye anomalies. The reported variant, absent in control databases, resulted in premature termination of protein synthesis, consistent with pathogenicity predictions. Both parents were identified as heterozygous carriers. Pregnancy termination was chosen post-diagnosis. Postmortem findings correlated with prenatal ultrasound. Our case broadens the prenatal phenotypic spectrum associated with MPDZ variants, necessitating further studies for comprehensive understanding of molecular mechanisms beneath the clinical manifestations.

Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia.

BACKGROUND: Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. METHODS: The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. RESULTS: The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein  expression  (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06). CONCLUSIONS: The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD.